Collaborative Research: DMS/NIGMS2: Discovering the Principles of Active Self-Organization in the Differentiating Genome Using Multi-Scale Modeling and In-Vivo Experiments

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Inside cells, the DNA exists in the functional form known as chromatin and resides inside the cell nucleus. Chromatin structure, organization and dynamics control all aspects of DNA biology. While the chemical structure of DNA and the rules by which genes are encoded are well understood, the physical principles governing the packing of DNA inside the cell nucleus remain an open question. During cell differentiation, the process by which stem cells become specialized, chromatin undergoes a complex rearrangement: In stem cells, all parts of DNA are accessible for processing such as gene expression. However, upon differentiation parts of the DNA that are not needed for the function of the specialized cell are condensed, whereas DNA parts actively used by the cell remain accessible, enabling the molecular machinery of the cell to reach the relevant genetic information. Understanding physical mechanisms that give rise to this reorganization of the differentiating genome is critical for many advances in modern biology and human medicine, but has been limited due to the very wide range of length and time scales involved in this process. The goal of this research is to uncover these complex mechanisms by integrating state-of-the-art live cell experiments with a suite of multiscale mathematical and computational models of the chromatin inside the nucleus. This project will also provide novel educational opportunities for graduate and undergraduate students, who will receive training in advanced imaging techniques and analysis, cell biology, polymer dynamics, fluid mechanics, as well as mathematical and computational modeling.This collaborative project will combine high-resolution live cell imaging experiments with mathematical and computational models to elucidate physical principles underlying chromatin dynamics and reorganization in the differentiating cell nucleus. In order to characterize the changes in genomic organization occurring during differentiation, experiments will be performed in live cells before and after differentiation. These experiments will guide the development of a novel coarse-grained computational model for chromatin dynamics in heterogeneous environments and of first-principles continuum theories capable of capturing the wide range of time and length scales in this problem. Experiments and mathematical modeling efforts will be closely integrated with the overarching goal of discovering the fundamental physical principles governing the reorganization of the differentiating genome.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.